Upregulation of the endothelin A (ETA) receptor and its association with neurodegeneration in a rodent model of glaucoma

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dc.creatorMcGrady, Nolan R.
dc.creatorMinton, Alena Z.
dc.creatorStankowska, Dorota L.
dc.creatorHe, Shaoqing
dc.creatorJefferies, Hayden B.
dc.creatorKrishnamoorthy, Raghu R.
dc.date.accessioned2022-09-30T17:34:17Z
dc.date.available2022-09-30T17:34:17Z
dc.date.issued2017-03-01
dc.description.abstractBACKGROUND: Primary open angle glaucoma is a heterogeneous group of optic neuropathies that results in optic nerve degeneration and a loss of retinal ganglion cells (RGCs) ultimately causing blindness if allowed to progress. Elevation of intraocular pressure (IOP) is the most attributable risk factor for developing glaucoma and lowering of IOP is currently the only available therapy. However, despite lowering IOP, neurodegenerative effects persist in some patients. Hence, it would be beneficial to develop approaches to promote neuroprotection of RGCs in addition to IOP lowering therapies. The endothelin system is a key target for intervention against glaucomatous neurodegeneration. The endothelin family of peptides and receptors, particularly endothelin-1 (ET-1) and endothelin B (ETB) receptor, has been shown to have neurodegenerative roles in glaucoma. The purpose of this study was to examine changes in endothelin A (ETA) receptor protein expression in the retinas of adult male Brown Norway rats following IOP elevation by the Morrison's model of ocular hypertension and the impact of ETA receptor overexpression on RGC viability in vitro. RESULTS: IOP elevation was carried out in one eye of Brown Norway rats by injection of hypertonic saline through episcleral veins. After 2 weeks of IOP elevation, immunohistochemical analysis of retinal sections from rat eyes showed an increasing trend in immunostaining for ETA receptors in multiple retinal layers including the inner plexiform layer, ganglion cell layer and outer plexiform layer. Following 4 weeks of IOP elevation, a significant increase in immunostaining for ETA receptor expression was found in the retina, primarily in the inner plexiform layer and ganglion cells. A modest increase in staining for ETA receptors was also found in the outer plexiform layer in the retina of rats with IOP elevation. Cell culture studies showed that overexpression of ETA receptors in 661W cells as well as primary RGCs decreases cell viability, compared to empty vector transfected cells. Adeno-associated virus mediated overexpression of the ETA receptor produced an increase in the ETB receptor in primary RGCs. CONCLUSIONS: Elevated IOP results in an appreciable change in ETA receptor expression in the retina. Overexpression of the ETA receptor results in an overall decrease in cell viability, accompanied by an increase in ETB receptor levels, suggesting the involvement of both ETA and ETB receptors in mediating cell death. These findings raise possibilities for the development of ETA/ETB dual receptor antagonists as neuroprotective treatments for glaucomatous neuropathy.
dc.description.sponsorshipThis work was supported by an extramural Grant to RRK from the National Eye Institute (EY019952) and from an intramural Grant from the UNT Health Science Center (RI6191). The first author, Mr. Nolan McGrady, was supported by a NIH training Grant (T32 AG 020494) awarded to the Neurobiology of Ageing training program.
dc.identifier.citationMcGrady, N. R., Minton, A. Z., Stankowska, D. L., He, S., Jefferies, H. B., & Krishnamoorthy, R. R. (2017). Upregulation of the endothelin A (ETA) receptor and its association with neurodegeneration in a rodent model of glaucoma. BMC neuroscience, 18(1), 27. https://doi.org/10.1186/s12868-017-0346-3
dc.identifier.issn1471-2202
dc.identifier.issue1
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31817
dc.identifier.volume18
dc.publisherBioMed Central Ltd.
dc.relation.urihttps://doi.org/10.1186/s12868-017-0346-3
dc.rights.holder© The Author(s) 2017.
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceBMC Neuroscience
dc.subjectEndothelin receptor A (ETA)
dc.subjectEndothelin receptor B (ETB)
dc.subjectEndothelin-1 (ET-1)
dc.subjectEndothelin-3 (ET-3)
dc.subjectIntraocular pressure (IOP)
dc.subjectNeurodegeneration
dc.subjectPrimary open angle glaucoma (POAG)
dc.subjectRetinal ganglion cells (RGCs)
dc.subject.meshAnimals
dc.subject.meshCell Survival / physiology
dc.subject.meshCells, Cultured
dc.subject.meshDependovirus / genetics
dc.subject.meshDisease Models, Animal
dc.subject.meshGenetic Vectors
dc.subject.meshGlaucoma / metabolism
dc.subject.meshGlaucoma / pathology
dc.subject.meshIntraocular Pressure / physiology
dc.subject.meshMale
dc.subject.meshNeurodegenerative Diseases / metabolism
dc.subject.meshNeurodegenerative Diseases / pathology
dc.subject.meshNeuroprotection / physiology
dc.subject.meshPhotoreceptor Cells, Vertebrate / metabolism
dc.subject.meshPhotoreceptor Cells, Vertebrate / pathology
dc.subject.meshReceptor, Endothelin A / genetics
dc.subject.meshReceptor, Endothelin A / metabolism
dc.subject.meshReceptor, Endothelin B / metabolism
dc.subject.meshRetinal Ganglion Cells / metabolism
dc.subject.meshRetinal Ganglion Cells / pathology
dc.subject.meshTransfection
dc.subject.meshUp-Regulation
dc.titleUpregulation of the endothelin A (ETA) receptor and its association with neurodegeneration in a rodent model of glaucoma
dc.typeArticle
dc.type.materialtext

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